Gamma-aminobutyric acid (GABA) is recognized as a major inhibitory neurotransmitter of the mammalian central nervous system. The discovery of specific receptors for GABA and for the benzodiazepines in 1977 was followed by discovering the interaction of the two receptors in 1978. These findings provide the first biochemical evidence for the support of a long-standing belief that some of the therapeutic effects of the benzodiazepines result from a facilitation of GABA receptor function.
Many clinical conditions are thought to arise, in part, from the imbalance between neurotransmission of GABA and those of other neurotransmitters. These conditions include Huntington's chorea, Parkinson's disease, spasticity, epilepsy, schizophrenia and tardive dyskinesia. Decreased GABA activity appears to contribute to the pathogenesis of these diseases. In addition, analgesia and satiety are thought to be regulated by GABA activity. Methods of modifying GABAergic neurotransmission are therefore desirable in order to modify these conditions.
Reduced GABA neuronal function can occur by the inhibition of GABA synthesis, by the blocking of the GABA receptors, or by the inhibition of chloride permeability. By reversing any or all of these functions, a therapeutic effect is possible. For instance, GABA agonists (which stimulate the GABA receptor), compounds which decrease GABA metabolism, and compounds which activate the GABA receptor by stimulating the benzodiazepine receptor have all been reported to inhibit a variety of induced seizure states. Several drugs, such as the benzodiazepines and progabide, have been found to be clinically effective as anticonvulsive agents, although many are limited or prevented in their use because of toxicity or secondary effects.
It is the object of this invention to provide novel compounds which demonstrate an ability to increase GABA and benzodiazepine binding and which also provide a therapeutic benefit in mammals having conditions derived from decreased GABA neuronal function but which avoid certain side effects and other undesirable attributes of compounds currently available for these disease states.